This invention relates to biologically active vitamin D compounds. More specifically, the invention relates to 21-norvitamin D compounds, to a general process for their preparation, and to their use in treating osteoporosis.
With the discovery of 1.alpha.,25-dihydroxyvitamin D.sub.3 as the active form of the vitamin has come an intense investigation of analogs of this hormonal form of vitamin D with the intent of finding analogs that have selective activity. By now, several compounds have been discovered which carry out the differentiative role of 1,25-dihydroxyvitamin D.sub.2 while having little or no calcium activity. Additionally, other compounds have been found that have minimal activities in the mobilization of calcium from bone while having significant activities in stimulating intestinal calcium transport. Modification of the vitamin D side chain by lengthening it at the 24-carbon has resulted in loss of calcium activity and either an enhancement or undisturbed differentiative activity. Placing the 24-methyl of 1.alpha.,25-dihydroxyvitamin D.sub.2 in the epi-configuration appears to diminish activity in the mobilization of calcium from bone. On the other hand, increased hydrophobicity on the 26--and 27--carbons seems to increase the total activity of the vitamin D compounds provided the 25-hydroxyl is present.
Several of these known compounds exhibit highly potent activity in vivo or in vitro, and possess advantageous activity profiles and thus are in use, or have been proposed for use, in the treatment of a variety of diseases such as renal osteodystrophy, vitamin D-resistant rickets, osteoporosis. psoriasis, and certain malignancies.
It is well known that females at the time of menopause suffer a marked loss of bone mass giving rise ultimately to osteopenia, which in turn gives rise to spontaneous crush fractures of the vertebrae and fractures of the long bones. This disease is generally known as postmenopausal osteoporosis and presents a major medical problem, both in the United States and most other countries where the life-span of females reaches ages of at least 60 and 70 years. Generally, the disease which is often accompanied by bone pain and decreased physical activity, is diagnosed by one or two vertebral crush fractures with evidence of diminished bone mass. It is known that this disease is accompanied by diminished ability to absorb calcium, decreased levels of sex hormones, especially estrogen and androgen, and a negative calcium balance.
Similar symptoms of bone loss characterize senile osteoporosis and steroid-induced osteoporosis, the latter being a recognized result of long term glucocorticoid (cortico-steroid) therapy for certain disease states.
Methods for treating the disease have varied considerably but to date no totally satisfactory treatment is yet known. A conventional treatment is to administer a calcium supplement to the patient. However, calcium supplementation by itself has not been successful in preventing or curing the disease. Another conventional treatment is the injection of sex hormones, especially estrogen, which has been reported to be effective in preventing the rapid loss of bone mass experienced in postmenopausal women. This technique, however, has been complicated by the fact of its possible carcinogenicity. Other treatments for which variable results have been reported, have included a combination of vitamin D in large doses, calcium and fluoride. The primary problem with this approach is that fluoride induces structurally unsound bone, called woven bone, and in addition, produces a number of side effects such as increased incidence of fractures and gastrointestinal reaction to the large amounts of fluoride administered. Another suggested method is to block bone resorption by injecting calcitonin or providing phosphonates.
U.S. Pat. No. 4,225,596 suggests the use of various metabolites of vitamin D.sub.3 for increasing calcium absorption and retention within the body of mammals displaying evidence of or having a physiological tendency toward loss of bone mass. The metabolites specifically named in that patent, i.e., 1.alpha.-hydroxyvitamin D.sub.3, 1.alpha.-hydroxyvitamin D.sub.2 1.alpha.,25-dihydroxyvitamin D.sub.3,1.alpha.,25-dihydroxyvitamin D.sub.2 and 1,24,25-trihydroxyvitamin D.sub.3, although capable of the activity described and claimed in that patent are also characterized by the disadvantage of causing hypercalcemia especially if used with the conventional calcium supplement treatment. Therefore, use of these compounds to treat osteoporosis has not been widely accepted. U.S. Pat. Nos. 3,833,622 and 3,901,928 respectively suggest using the hydrate of 25-hydroxyvitamin D.sub.3 and 1.alpha.-hydroxyvitamin D.sub.3 for treatment of osteoporosis in a general expression of utility for those compounds. It is well known both of those compounds express traditional vitamin D-like activity, including the danger of hypercalcemia.
U.S. Pat. No. 4,588,716 also suggests the use of 1.alpha., 25-dihydroxy-24-epi-vitamin D.sub.2 to treat bone disorders characterized by the loss of bone mass, such as osteoporosis. This compound expresses some of the vitamin D-like characteristics affecting calcium metabolism such as increasing intestinal calcium transport and stimulating the mineralization of new bone. It has the advantage of minimal effectiveness in mobilizing calcium from bone. The 24-epi compound may be administered alone or in combination with a bone mobilization inducing compound such as a hormone or vitamin D compound such as 1.alpha.-hydroxyvitamin D.sub.3 or D.sub.2 or 1.alpha.,25-dihydroxyvitamin D.sub.3 or D.sub.2.
U.S. Pat. No. 5,194,431 discloses the use of 24-cyclopropane vitamin D.sub.2 compounds in treating osteoporosis. Also, U.S. Pat. No. 4,851,401 discloses the use of cyclopentano 1,25-dihydroxyvitamin D.sub.3 compounds in the treatment of osteoporosis and related diseases.
In an ongoing effort to develop a treatment for osteoporosis, the carbon 20 position of the side-chain was investigated to determine its potential. Altering the order of substituents or the substitution pattern on carbon 20 could result in a change of minimum energy position for conformations around the C.sub.17 -C.sub.20 bond, and consequently, in a change of side-chain orientation with respect to the ring system. Orientation of the side-chain with respect to the ring system and configuration on the C.sub.20 may have important consequences for biological properties of cholestane derivatives, in particular vitamin D compounds. It is well documented that binding of 1.alpha.,25-dihydroxyvitamin D.sub.3 (1, Scheme 1) involves active centers in the ring A and triene system as well as in the side-chain. Altering the "normal configuration" around C.sub.7 -C.sub.20 bond in vitamin D could change the distance between active centers within the molecule, and thus result in a change in activity of such compounds.
A synthesis of 1.alpha.,25-dihydroxy-21 -norvitamin D.sub.3 was described in Kuboderal et al, "Synthetic Studies of Vitamin D Analogs. X. Synthesis and Biological Activities of 1.alpha.,25-Dihydroxy-21-Norvitamin D.sub.3 ", Chem. Pharm. Bull., 40(3) 648-651 (1992) from 1.alpha.-hydroxydehydroepiandrosterone. Certain biological properties of 1.alpha.,25-dihydroxy-21-norvitamin D.sub.3 were also examined and compared with those of 1.alpha.,25-dihydroxyvitamin D.sub.3 and 1.alpha.,25-dihydroxy-21-nor-20-oxavitamin D.sub.3 to evaluate the effect of the 21-methyl substituent on biological properties.